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) (51) International Patent Classification: Columbia V5G 1G3 ) ( (51) International Patent Classification: Columbia V5G 1G3 (CA). PANDEY, Nihar R.; 10209 A 61K 31/4525 (2006.01) C07C 39/23 (2006.01) 128A St, Surrey, British Columbia V3T 3E7 (CA). A61K 31/05 (2006.01) C07D 405/06 (2006.01) (74) Agent: ZIESCHE, Sonia et al.; Gowling WLG (Canada) A61P25/22 (2006.01) LLP, 2300 - 550 Burrard Street, Vancouver, British Colum¬ (21) International Application Number: bia V6C 2B5 (CA). PCT/CA2020/050165 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection av ailable) . AE, AG, AL, AM, 07 February 2020 (07.02.2020) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (26) Publication Language: English HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 16/270,389 07 February 2019 (07.02.2019) US OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (63) Related by continuation (CON) or continuation-in-part SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, (CIP) to earlier application: TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. US 16/270,389 (CON) (84) Designated States (unless otherwise indicated, for every Filed on 07 Februaiy 2019 (07.02.2019) kind of regional protection available) . ARIPO (BW, GH, (71) Applicant: MEDIPURE PHARMACEUTICALS INC. GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, [CA/CA]; 302 - 267 West Esplanade Ave, North Vancou¬ UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, ver, British Columbia V7M 1A5 (CA). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventors: TIWARI-PANDEY, Rashmi; 10209 128A St, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Surrey, British Columbia V3T 3E7 (CA). KODEKALRA, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, Rakshit Devappa; 5291 Norfolk Street, Burnaby, British KM, ML, MR, NE, SN, TD, TG). (54) Title: CANNABINOID RECEPTOR AGONISTS AND SERINE HYDROLASE ENZYME INHIBITOR BASED ANXIOLYTIC THERAPEUTIC PRODUCT Figure 1 (57) Abstract: Provided herein are formulations for treating affective mood disorders. The formulations comprise one or more than one CB receptor agonist and one or more than one serine hydrolase enzyme inhibitor. [Continued on next page] Published: with international search report (Art. 21(3)) with amended claims (Art. 19(1)) in black and white; the international application as fded contained color or greyscale and is available for download from PATENTSCOPE CANNABIN OID RECEPTOR AGONISTS AND SERINE HYDROLASE ENZYME INHIBITOR BASED ANXIOLYTIC THERAPEUTIC PRODUCT FIELD OF INVENTION [0001] This disclosure relates to formulations for treating mood disorders. Specifically, the present disclosure is related to formulations that combine one or more than one cannabinoid receptor agonist and one or more than one serine hydrolase enzyme inhibitor to treat mood disorders. BACKGROUND OF THE INVENTION [0002] Anxiety stems from and perpetuates dysregulation of neurobiological systems, but the exact mechanisms of anxiety disorders are still only partially understood. Low levels of gamma-aminobutyric acid (GABA), a neurotransmitter that reduces activity in the central nervous system, contribute to anxiety. A number of anxiolytics achieve their effect by modulating the GABA receptors. [0003] The GABA receptors are a class of receptors that respond to GABA, which is the chief inhibitory neurotransmitter in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABA A (or GABA (A)) and GABA B (or GABA(B)). GABA A receptors are ligand-gated ion channels (also known as ionotropic receptors), whereas GABA B receptors are G protein-coupled receptors (also known as metabotropic receptors). [0004] All GABA A receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for GABA, while a subset of GABA A receptor complexes also contain a single binding site for benzodiazepines. Binding of benzodiazepines to this receptor complex does not alter binding of GABA. Unlike other positive allosteric modulators that increases ligand binding, benzodiazepine binding acts as a positive allosteric modulator by increasing the total conduction of chloride ions across the neuronal cell membrane when GABA is already bound to its receptor. Therefore, benzodiazepines enhance the effect of GABA at the GABA A receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti anxiety), anticonvulsant, and muscle relaxant properties. [0005] While benzodiazepine products have been in the market to treat anxiety and associated mood disorders for some time, their use by many patients is poorly tolerated and include side effects such as: drowsiness, dizziness, decreased alertness and concentration, decreased libido, erection problems, depression, disinhibition, nausea, changes in appetite, blurred vision, confusion, euphoria, depersonalization, nightmares, liver toxicity, aggression, violence, impulsivity, irritability, suicidal behavior, seizures in people with epilepsy, anterograde amnesia, confusion, ataxia, hangover effects, falls, benzodiazepine dependence, and benzodiazepine withdrawal syndrome. [0006] Cannabis has been used as an anxiolytic, however the use has been limited to dry plant product which is smoked or a crude or standardized extract containing a mixture of uncharacterized phytochemical bioactives, including psychoactive cannabinoids such as tetrahydrocannabinol (THC) at concentrations which may produce negative side effects such as decrease in short-term memory, dry mouth, impaired motor skills, reddening of the eyes, increased heart rate, increased appetite and consumption of food, lowered blood pressure, impairment of short-term and working memory, reduced psychomotor coordination and concentration, and an increased risk of developing schizophrenia with adolescent use. [0007] Cannabinoids are a class of diverse chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain. Ligands for these receptor proteins include the endocannabinoids (produced naturally in the body by humans and animals), the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured artificially). Over 100 different cannabinoids have been isolated from cannabis, exhibiting varied effects [1]. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis mentioned above. Cannabidiol (CBD), one major non-psychotomimetic compound of the plant, shows psychological effects substantially different from those of THC, by having anxiolytic effects both in humans and in animals. [0008] Oral administration of CBD to healthy volunteers has been shown to attenuate the anxiogenic effect of THC and does not seem to involve any pharmacokinetic interactions [2] In animal studies, CBD has similar effects to anxiolytic drugs in different paradigms including conditioned emotional response, the Vogel conflict test, and the elevated plus-maze test [3] In human studies, the anxiolytic effects of CBD have been elicited in subjects submitted to the Simulation Public Speaking Test (SPST) [4] No signs of toxicity or serious side effects have been observed following chronic administration of cannabidiol to healthy volunteers [5], even in large acute doses of 700 mg/day [6] [0009] There are currently no cannabinoid prescription products on the market to treat mood disorders, particularly anxiety. [0010] The endocannabinoid system (ECS) is a group of endogenous cannabinoid receptors located in the mammalian brain and throughout the central and peripheral nervous systems, consisting of neuromodulatory lipids and their receptors. The ECS is involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory, and in mediating the psychoactive effects of cannabis. Two primary endocannabinoid receptors have been identified: CB1 and CB2. CB1 receptors are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the endocannabinoid ligand Anandamide (AEA), as well as its mimetic phytocannabinoid, delta 9-tetrahydrocannabinol (THC). Cannabinoids such as psychoactive THC activate CB1 and CB2 receptors, but mainly exhibits its neuro-behavioural effects by interacting with CB1 receptors. CB1 agonism produces medicinally useful activities, such as analgesia, but also a number of undesirable side effects, including locomotor and cognitive impairments, as well as abuse liability. To date, it has proved difficult to uncouple these beneficial and untoward properties, thus limiting the therapeutic utility of direct CB1 agonists. [0011] One other main endocannabinoid is 2-Arachidonoylglycerol (2-AG) which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoid, CBD. 2-AG and CBD are involved in the regulation of appetite, immune system functions and pain management. [0012] Endogenous cannabinoids (i.e., endocannabinoids), such as AEA and 2-AG, are produced throughout the limbic system and other brain regions associated with emotionality and are believed to modulate behavioral responses to stress-related conditions. Inhibition of AEA and
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